The fundamental objective of this proposal is to elucidate the etiology of papillomatosis and related malignancies. During the tenure of the previous grantng period we have employed a molecular approach to determine whether clinical cases of recurring or chronic wart disease are caused by a specific type of human papillomayvirus(HPV) and whether this virus type could be found associated with malignancies that occupy similar anatomical sites and appear to have arisen from such papillomas. Our studies have not only demonstrated the presence of HPV DNA in several papilloma syndromes in which HPV had been previously identified, but have also identified HPV-related nucleotide sequences in two wart-related malignancies, epidermody splasia verruciformis (EV) and verrucous carcinoma. In this renewal application we plan to: 1) continue our analysis of papillomas for the presence of unique HPV, particularly those which exhibit a propensity to progress to carcinomas such as adenomatous polyps, multiple familial polyposis, urinary bladder polyps and cervical warts; 2) determine the nature and status (i.e. ntegrated or unintegrated) of the HPV DNA-associated with EV and verrucous carcinomas; and, 3) examine the expression of HPV in benign tissue and wart related-malignant tissue in an effort to determine whether specific HPV genetic sequences are expressed during, and therefore possible responsible for, malignant conversion. Our ultimate goals therefore are to delineate the species of HPV responsible for chronic wart disease and wart-related malignancies, the nature of the HPV DNA genome involved, and the molecular mechanism(s) and specific HV geetic sequences responsible for this phenomenon. The methodologies that we plan to employ to achieve these objectives are, for the most part, already implemented in our laboratory and include a variety of physico-chemical, enzymological, and filter-hybridization techniques available for the analysis of DNA, RNA, and protein including nucleotide sequence analysis.